title: Mitochondrial fusion directs cardiomyocyte differentiation via calcineurin and Notch signaling.
abstract: Mitochondrial morphology is crucial for tissue homeostasis, but its role in cell differentiation is unclear. We found that mitochondrial fusion was required for proper cardiomyocyte development. Ablation of mitochondrial fusion proteins Mitofusin 1 and 2 in the embryonic mouse heart, or gene-trapping of Mitofusin 2 or Optic atrophy 1 in mouse embryonic stem cells (ESCs), arrested mouse heart development and impaired differentiation of ESCs into cardiomyocytes. Gene expression profiling revealed decreased levels of transcription factors transforming growth factor-β/bone morphogenetic protein, serum response factor, GATA4, and myocyte enhancer factor 2, linked to increased Ca(2+)-dependent calcineurin activity and Notch1 signaling that impaired ESC differentiation. Orchestration of cardiomyocyte differentiation by mitochondrial morphology reveals how mitochondria, Ca(2+), and calcineurin interact to regulate Notch1 signaling.
authors.affiliation: Department of Cell Physiology and Metabolism, University of Geneva, 1206 Geneva, Switzerland.
authors.forename: Atsuko
authors.initials: A
authors.lastname: Kasahara
authors.forename: Sara
authors.initials: S
authors.lastname: Cipolat
authors.forename: Yun
authors.initials: Y
authors.lastname: Chen
authors.forename: Gerald W
authors.initials: GW
authors.lastname: Dorn
authors.forename: Luca
authors.initials: L
authors.lastname: Scorrano
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000378:metabolism*; D065095:Calcineurin Inhibitors; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology*; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D006321:Heart / Q000196:embryology; D051379:Mice; D018345:Mice, Knockout; D063154:Mitochondrial Dynamics / Q000235:genetics / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000648:ultrastructure; D051881:Receptor, Notch1 / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D065095:Calcineurin Inhibitors; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; D014157:Transcription Factors; D019703:Calcineurin; D020558:GTP Phosphohydrolases; C488750:Mfn1 protein, mouse; C488751:Mfn2 protein, mouse; C498809:Opa1 protein, mouse